1. Field of The Invention
This invention generally relates to techniques for inducing immune tolerance using an immunotoxin. In particular, this invention relates to the use of immune tolerance inducing techniques with pancreatic islet transplantation, for the purpose of inhibiting rejection of the transplant. This invention further relates to the treatment of diabetes using immune tolerance inducing techniques in conjunction with pancreatic islet transplantation.
2. Background Art
There are 16 million diabetics within the United States. Ninety percent of these have Type II diabetes, which is defined by hyperglycemia in the face of normal or elevated levels of circulating insulin. As Type II diabetes progresses, however, a decrease in circulating level of insulin may occur as the beta cells of the pancreatic islets produce and secrete less insulin. The mechanism of insulin resistance in Type II diabetes has not been elucidated, and the condition has proved to be difficult to treat and is currently the leading cause of renal failure in this country.
Type I diabetes results from pancreatic islet beta cell destruction and loss of insulin secretion secondary to an autoimmune process. Type I diabetes generally can be controlled by close monitoring of blood glucose concentration and multiple daily injections of exogenous insulin. Nonetheless, even with insulin replacement therapy, euglycemia is not achieved and at least one half of the Type I population cannot achieve sufficient control to prevent the complications of retinopathy, vasculopathy, and renal deterioration (71,72).
Allografts of pancreatic islets from cadaveric donors have been considered to offer a potential cure for Type I diabetes. Although reversal of type II diabetes by an islet xenograft transplant was described in one study in rodents (74), the conventional wisdom has been that this treatment would only work when insulin secretion was subnormal. In fact clinical tests of islet transplantation have been limited largely to type I diabetics and patients who have previously undergone total pancreatectomy (75).
Even treatment of Type I diabetes with pancreatic islet allografts, however, has not been effective in freeing most patients from exogenous insulin injections (71,73). The problem has been that the immunosuppressive reagents required to inhibit allograft rejection can severely compromise transplanted islet cell function (71). This is unlike the case of renal transplantation where cyclosporine A and corticosteroid derivatives do not severely compromise kidney function, in the majority of cases.
Transplant tolerance remains an elusive goal for patients and physicians whose ideal would be to see a successful, xenogeneic pancreatic islet transplant performed without the need for indefinite, non-specific maintenance immunosuppressive drugs and their attendant side effects. As with many transplant procedures, securing viable allogeneic grafts can be difficult. In addition, long term immunosuppression can be problematic.
Over the past 10 years the majority of transplant recipients have been treated with cyclosporin, azathioprine, and prednisone with a variety of other immunosuppressive agents being used as well for either induction or maintenance immunosuppression. The average annual cost of maintenance immunosuppressive therapy in the United States is approximately $10,000. In addition to the cost, these agents, because of their non-specific effects, have considerable side effects, including compromising islet cell function and increasing susceptibility to infection. A major goal in pancreatic islet transplant immunobiology is the development of specific immunologic tolerance to pancreatic transplants with the potential of freeing patients from the side effects of continuous pharmacologic immunosuppression and its attendant complications and costs.
Anti-T cell therapy (anti-lymphocyte globulin) has been used in rodents in conjunction with thymic injection of donor cells (Posselt et al. Science 1990; 249: 1293–1295 and Remuzzi et al. Lancet 1991; 337: 750–752). Thymic tolerance has proved successful in rodent models and involves the exposure of the recipient thymus gland to donor alloantigen prior to an organ allograft from the same donor. However, thymic tolerance has never been reported in large animals, and its relevance to tolerance in humans in unknown.
One approach to try to achieve such immunosuppression has been to expose the recipient to cells from the donor prior to the transplant, with the hope of inducing tolerance to a later transplant. This approach has involved placement of donor cells (e.g. bone marrow) presenting MHC Class I antigens in the recipient's thymus shortly after application of anti-lymphocyte serum (ALS) or radiation. However, this approach has proved difficult to adapt to live primates (e.g. monkeys; humans). ALS and/or radiation render the host susceptible to disease or side-effects and/or are insufficiently effective.
If a reliable, safe approach to specific immunologic tolerance to pancreatic islet transplantation, particularly xenogeneic transplantation, could be induced, this would be of tremendous value and appeal to patients and transplant physicians throughout the world with immediate application to new transplants and with potential application to existing transplants in recipients with stable transplant function. Thus, a highly specific immune tolerance inducement is desired. Furthermore, there is a need for a means for imparting tolerance in primates, without the adverse effects of using ALS or radiation. Moreover, the goal is to achieve more than simply delaying the rejection response. Rather, an important goal is to inhibit the rejection response to the point that rejection is not a factor in reducing average life span among transplant recipients.
The present invention meets these needs by providing a method of inducing immune tolerance to pancreatic islet transplantation.